Methods and compositions relating to treatment of cns diseases

Abstract

Described herein are methods relating to the treatment of certain diseases with an agonist of Mfsd2A, and the treatment of certain other diseases with an inhibitor of Mfsd2A.

1 . A method of treating a disease selected from the group consisting of:
 a) a primary central nervous cancer or a metastatic disease in the central nervous system;   b) a neuroinflammatory disorder;   c) a neurocognitive disorder;   d) a neurovascular disease; and   e) a retinal disease;   in a subject in need thereof, the method comprising administering to the subject an agonist of Mfsd2A.   
     
     
         2 . The method of  claim 1 , wherein
 a) the primary central nervous cancer or metastatic disease in the central nervous system is selected from the group consisting of: glioblastoma, CNS lymphoma, meningioma, metastatic melanoma, metastatic breast cancer, metastatic lung cancer, metastatic renal cell cancer, and metastatic colorectal cancer;   b) the neuroinflammatory disorder is selected from the group consisting of: multiple sclerosis, infectious encephalitis, COVID-19 encephalopathy, sepsis, and CAR-T neurotoxicity (ICANS) and other toxicities from immuno- and cancer therapeutics;   c) the neurocognitive disorder is selected from the group consisting of: Alzheimer's disease, Huntington disease, Lewy-Body Dementia, and frontotemporal dementia (FTD);   d) the neurovascular disease is selected from the group consisting of: stroke, trauma, and cerebral edema; and   e) the retinal disease is selected from a group consisting of: diabetic retinopathy, macular degeneration, macular edema, retinitis pigmentosa, infectious retinitis, and inflammatory retinitis.   
     
     
         3 . The method of  claim 1 , wherein the disease is glioblastoma. 
     
     
         4 . The method of  claim 1 , wherein the subject is not further administered a chemotherapeutic. 
     
     
         5 . The method of  claim 1 , wherein the subject is not further administered a further therapeutic agent. 
     
     
         6 . The method of  claim 1 , wherein the agonist is a small molecule agonist. 
     
     
         7 . The method of  claim 1 , wherein the agonist is a pharmaceutical, nutraceutical or dietary formulation, or dietary supplement comprising omega-3 fatty acids and/or linolenic acid. 
     
     
         8 . The method of  claim 1 , wherein the agonist is a cholesterol lowering drug. 
     
     
         9 . The method of  claim 1 , wherein the agonist is a Mfsd2A polypeptide or a vector encoding a Mfsd2A polypeptide. 
     
     
         10 . The method of  claim 8 , wherein the vector is a CNS endothelial-targeting AAV. 
     
     
         11 . The method of  claim 9 , wherein the CNS endothelial-targeting AAV is PHP.V1, BI-30, BR1, or a variant thereof. 
     
     
         12 . The method of  claim 1 , wherein the agonist is targeted to endothelial cells. 
     
     
         13 . A method of treating a disease selected from the group consisting of:
 a) a primary central nervous cancer or a metastatic disease in the central nervous system;   b) a neuroinflammatory disease;   c) a neurocognitive disorder;   d) a neuropsychiatric condition;   e) a movement disorder;   f) a critical illness;   g) an enzyme deficiency disorder; and   h) a lysosomal storage disorder.   in a subject in need thereof, the method comprising administering to the subject:   i) an inhibitor of Mfsd2A; and   ii) a central nervous system therapeutic agent.   
     
     
         14 . The method of  claim 13 , wherein:
 a) the primary central nervous cancer or metastatic disease in the central nervous system is selected from the group consisting of: glioblastoma, CNS lymphoma, meningioma, metastatic melanoma, metastatic breast cancer, metastatic lung cancer, metastatic renal cell cancer, and metastatic colorectal cancer;   b) the neuroinflammatory disease is selected from the group consisting of: Multiple Sclerosis (MS), neuromyelitis optica (NMO) Spectrum Disorder, autoimmune encephalitis, infectious meningoencephalitis, progressive multifocal leukoencephalopathy (PML), and paraneoplastic encephalitis;   c) the neurocognitive disorder is selected from the group consisting of: Alzheimer's Dementia, Lewy-Body Dementia, Frontotemporal Dementia, Encephalopathy, and Vascular Demential;   d) the neuropsychiatric condition is selected from the group consisting of: Schizophrenia, Major Depressive Disorder, Attention-Deficit/Hyperactivity Disorder, and Bipolar Disorder;   e) the movement disorder is selected from the group consisting of: Parkinson's Disease, Dystonia, ALS, and Tic disorders;   f) the critical illness is selected from the group consisting of: trauma, stroke, seizure disorders such as epilepsy;   g) the enzyme deficiency disorder is selected from a lysosomal storage disorder, CDKL5 deficiency disorder, X-linked severe paediatric monogenic developmental and epilepsy disorder occurring via a loss of function mutation; and   h) the lysosomal storage disorder is selected from the group consisting of: Tay-Sachs disease, Pompe disease, Gaucher disease, Neimann-Pick disease, Fabry disease, and Mucopolysaccharidoses (MPS) disease.   
     
     
         15 . The method of  claim 13 , wherein the inhibitor is a small molecule inhibitor. 
     
     
         16 . The method of  claim 13 , wherein the inhibitor is an anti-Mfsd2A antibody reagent, an inhibitory nucleic acid, or a vector encoding an inhibitory nucleic acid. 
     
     
         17 . The method of  claim 16 , wherein the inhibitory nucleic acid comprises or consists of the sequence of one or more of SEQ ID NOs: 16-19. 
     
     
         18 . The method of  claim 16 , wherein the vector is a CNS endothelial-targeting AAV. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 13 , wherein the central nervous system therapeutic agent is administered at least 10 days after the inhibitor of Mfsd2A is first administered. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 13 , wherein the inhibitor of Mfsd2A is administered for at least 3 months. 
     
     
         24 .- 46 . (canceled)